Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aß aggregation.

Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease.

In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure-activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC50 = 0.96 ± 0.14 µM, BChE IC50 = 1.23 ± 0.23 µM) compared to earlier identified lead molecule EJMC-G (AChE IC50 = 5.74 ± 0.13 µM, BChE IC50 = 14.05 ± 0.10 µM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC50 = 20.25 ± 0.26 µM) over the earlier identified EJMC-B (IC50 = 61.98 ± 0.30 µM) and it also was able to chelate iron. Co-treatment of 13b with H2O2, significantly attenuated and reversed H2O2-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

A review on iron chelators as potential therapeutic agents for the treatment of Alzheimer's and Parkinson's diseases.

Iron plays a vital role in several cellular functions due to its unique physiochemical properties. Iron concentration increases in the brain with age due to multiple factors. Excessive amount of iron can lead to formation of reactive oxygen species. Neurodegenerative disorders are characterized by iron supplemented increase in oxidative stress and cellular damage. There is an urgent need of novel therapies which should not only provide symptomatic relief but also be able to modulate iron accumulation in the brain. Therefore, the development of novel iron chelators as neuroprotective agents for the treatment of neurodegeneration is an emerging trend. Several iron chelators including 8-hydroxyquinoline derivatives, dopaminergic agonists and natural products are under preclinical and clinical investigations for the treatment of neurodegenerative disorders.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid ß (Aß) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheses have been proposed, including the cholinergic, Aß, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aß hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

Design, Synthesis, and Biological Evaluation of Ferulic Acid-Piperazine Derivatives Targeting Pathological Hallmarks of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aß and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed 13a, harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aß1-42 aggregation in various AD models. 13a exhibited promising anticholinesterase activity against AChE (IC50 = 0.59 ± 0.19 µM) and BChE (IC50 = 5.02 ± 0.14 µM) with excellent antioxidant properties in DPPH assay (IC50 = 5.88 ± 0.21 µM) over ferulic acid (56.49 ± 0.62 µM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, 13a turned out to be a promising molecule that can efficiently cross the blood-brain barrier. Notably, 13a also exhibited iron-chelating properties. Furthermore, 13a effectively inhibited self- and metal-induced Aß1-42 aggregation. It is worth mentioning that 13a demonstrated no symptom of cytotoxicity up to 30 µM concentration in PC-12 cells. Additionally, 13a inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. 13a could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, 13a was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, 13a notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that 13a holds promise as a potential candidate for further development in AD management.

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review.

Alzheimer's disease (AD) is a chronic age-related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability of an individual. The exact pathophysiology of AD is not fully understood. However low level of the neurotransmitter named acetylcholine (ACh), aggregation of Aß peptide into toxic Aß plaque, hyperphosphorylation of tau, bio-metal imbalance, and oxidative stress are the main hallmarks of this disease. Due to the complex pathophysiology of AD, no specific treatment is available in the market, and treatment is only limited to the symptomatic relief. So, there is an urgent need for the development of new drug candidate, which can have disease-modifying effect and improve learning and memory in AD patient. Therefore, berberine-based multifunction compounds with potential cholinesterase inhibitory properties were reviewed in this article. Structure-activity relationship (SAR) and biological activity provide highlights on the new derivatives used for the management of AD.

Rationalizing mineral gypsum use through microbially enriched municipal solid waste compost for amelioration and regaining productivity potential of degraded alkali soils.

Reclamation of alkali soils to harness their productivity potential is more complex due to the presence of excess sodium ions, poor hydraulic conductivity and infiltration rate, resulting in poor plant growth and crop productivity. Sodic soil reclamation using inorganic ameliorants like mineral gypsum or phosphogypsum is beyond the reach of small and marginal farmers having alkali soils because of their higher market prices and shortage of availability. Conjoint use of inorganic and organic amendments can be a pragmatic solution for improving soil physico-chemical and biological properties and sustaining crop productivity. Municipal solid waste compost (MSWC) available in abundant quantity if enriched with the efficient halophilic microbial consortium and used in conjunction with a reduced dose of gypsum can be a cost-effective approach for sustainable reclamation of alkali soils and harnessing their productivity potential. Hence, a field experiment was conducted on a high alkali soil (pH2 9.2 ± 0.10), electrical conductivity (EC) 1.14 ± 0.12 dS m-1, exchangeable sodium percentage 48 ± 2.50 and organic carbon (0.30%) was conducted during 2018-19 to 2020-21 to study the combined effect inorganic and organic (enriched municipal solid waste compost (EMSWC)) amendments on amelioration of alkali soils and sustaining productivity of rice-wheat cropping system. Application of gypsum @ 25% GR + enriched MSW compost @ 10 t ha-1 (T6) showed significant improvement in soil physico-chemical and biological properties over the sole application of organic (T3 and T4), inorganic (T2) and control (T1). A significant improvement in soil fertility status in terms of available nitrogen and micronutrients as well as CO3, HCO3, Cl, Ca and Mg content were recorded with the combined application of organic and inorganic soil amendments (T5 and T6) over the sole application of mineral gypsum. Soil microbial biomass carbon (MBC), nitrogen (MBN) and phosphorus (MBP) improved significantly due to the application of EMSWC with gypsum over the application of gypsum only. Grain yield of rice and wheat increased significantly (P < 0.05) owing to the application of a reduced dose of gypsum (25% GR) and EMSWC @ 10 t ha-1 (T6) with values of 5.55 and 3.83 t ha-1, respectively over rest of the treatments. Three years economic analysis of the study revealed that treatments T6 and T5 gave the highest positive net return whereas it was lowest in treatment T1 and negative in treatment T2. The highest benefit-to-cost ratio (B:C) was obtained in treatments T6 and T5 which were significantly higher compared to the rest of the treatments.

Prevalence of bovine brucellosis in India: a meta-analysis.

BACKGROUND: Bovine brucellosis is a highly contagious zoonotic disease that hinders production and is a vital public health concern. Even though brucellosis is one of the important diseases in India, the exact prevalence details of the disease are not known. OBJECTIVE: To derive an estimate of the prevalence of brucellosis in India. MATERIAL AND METHODS: A systematic review and meta-analysis were carried out by using PRISMA and MOOSE protocols. A total of 133 studies were taken from online sources and various publications. Among these, 69 studies were incorporated that include a total of 140908 bovines. The data were compiled from 1990 to 2019 around India. RESULTS: Pooled estimates of the prevalence of brucellosis in cattle and buffaloes were 16.6% (95% CI: 13.0, 21.1) and 14.2% (95% CI: 8.9, 21.8), respectively and in bovines was 15.1% (95% CI: 12.0, 18.8). The meta-analysis revealed that there was significant heterogeneity between the published studies. CONCLUSION: As the prevalence of bovine brucellosis in India is not known hence the present study will provide the knowledge on prevalence and epidemiology of bovine brucellosis in India and will be helpful for the government to make policy plans to control this disease in India.

Conservation Tillage and Waste Crop Residue Based Zinc Fortification in Rice and Wheat under Reclaimed Sodic Soils: Progress toward Nutrient Circularity and Sustainability.

Nearly 50% of the population across the globe is at risk of malnutrition with respect to zinc (Zn) in areas where a cereal based dietary system dominates. The present study estimated daily Zn intake in humans through field experiments in reclaimed sodic soil, utilizing waste crop residue (CR) in conservation tillage where CR played a vital role in enhancing Zn uptake in rice and wheat grains. Zn dynamics, its bioavailability, interaction with soil properties, and plausible contribution in dietary intake were studied extensively to supplement the research. A higher mobility factor (2.70%) and plant available Zn resulted in its higher uptake in rice (58.2 mg kg-1) and wheat (67.2 mg kg-1) under zero tillage in rice followed by zero tillage in wheat where CR was retained on the surface (ZTR-ZTW+CR). Daily Zn intake was found to be maximum (0.651 mg kg-1 day-1) under ZTR-ZTW+CR, demonstrating zinc sufficiency. Thus, this study may help in formulating actionable policies for combating both nutritional security and environmental hazards due to CR burning.

Prevalence of babesiosis in bovines of India: a meta-analytical approach for 30 years (1990-2019).

BACKGROUND: India has a massive population of bovines, which makes the framework of the economy mainly relying on milk and meat production. Parasitic diseases such as babesiosis are detrimental to bovines by decreasing animal welfare and production efficiency. AIM: Performing a meta-analysis of the prevalence of babesiosis over 30 years viz 1990 to 2019 within India to pool out individual studies from different country regions. MATERIAL AND METHODS: The studies were reviewed thoroughly to assess the quality, and it was done by following the preferred reporting items for systematic review and meta-analysis (PRISMA) and MOOSE protocols. The prevalence of babesiosis in cattle and buffaloes was calculated using meta-analysis tools using R-software and Q Statistics. RESULTS: The systematic review and meta-analysis performed on 47 studies among bovine, 48 studies among cattle, and 13 studies among buffaloes revealed the (pooled) prevalence of babesiosis in India as 10.9% (6.3%-18.2%; Q = 5132.03, d.f. = 46, P < 0.001), 11.9% (6.9%-19.8%; Q = 5060.2, d.f.=47, P < 0.001), and 6.0% (2.6%-13.2%; Q = 500.55, d.f.=12, P < 0.001), respectively, which provides a rather exact scenario of the prevalence of this haemoparasitic disease across the country. In addition, cattle were having higher risk of babesiosis than buffalo. CONCLUSION: The findings from the meta-analysis showed that the disease is prevalent across the country, and that bovines are highly affected by it. CLINICAL RELEVANCE: Appropriate prevention and control measures should be taken to mitigate this disease and enhance welfare and production performances of bovines.

Drug repurposing for Alzheimer's disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors.

Alzheimer's disease (AD) is one of the most familiar multifactorial and complex neurodegenerative disorders characterized by loss of cholinergic neurons in the brain. The various attempts for drug development to treat AD have been hampered by largely unsuccessful clinical trials in the last two decades. Developing a new drug from scratch takes enormous amounts of time, effort and money, mainly due to several barriers in the therapeutic drug development process. Drug repurposing strategy resuscitates this slow drug discovery process by finding new uses and clinical indications for existing drugs. This study is focused on the cholinergic hypothesis, a well-established target of the clinically available drugs in the market for the treatment of AD. The computational virtual screening (VS) led to the identification of thiazolidinedione (TZD, antidiabetic) and aminoquinoline (antimalarial) class of drugs as acetylcholinesterase (AChE) inhibitors. Intriguingly, rosiglitazone (RGZ) and hydroxychloroquine (HCQ) were found to be mild-to-moderate inhibitors of hAChE (human acetylcholinesterase) in our enzyme inhibition studies which are complementary to our computational studies. On the basis of our computational and experimental studies, it can be suggested that the beneficial effect of RGZ and HCQ in AD patients reported in the literature may partly be due to their AChE inhibitory property. The VS also led to the identification of antifungal drugs miconazole and oxiconazole as potential AChE inhibitors. The molecular dynamics (MD) simulation of the potential hits belonging to TZD, aminoquinoline and azoles class were also carried out. The MD simulations studies revealed detailed computational insights related to molecular interactions and protein-ligand stability for selected hits.

Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid ß Induced Neurotoxicity in Alzheimer's Disease Models.

The pathological hallmarks of Alzheimer's disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-ß protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aß1-42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivoDrosophila model by rescuing eye phenotypes from degeneration caused by Aß toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aß1-42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting Aß1-42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management.

Evaluation of Gingival Crevicular Fluid and Serum Tartrate-resistant Acid Phosphatase Levels in Subjects with Clinically Healthy Periodontium and Chronic Periodontitis - A Clinico-biochemical Study.

BACKGROUND: Periodontitis is a chronic inflammatory disease with conglomerate etiology making it difficult to diagnose at the early stages. Potential biomarkers in gingival crevicular fluid (GCF) would determine the presence of the current disease activity, predict sites vulnerable for future breakdown, and assess the response to periodontal interventions. Merely elevated levels of inflammatory soft-tissue markers do not indicate bone destruction. Since there is no single ideal biomarker established, bone-related biomarkers such as telopeptide of type I collagen, osteocalcin, calprotectin, osteopontin, and tartrate-resistant acid phosphatase (TRAP) seem to hold great promise as predictive markers to determine bone destruction and active phases in the disease progression. The present study is intended to explore the biologic plausibility of the levels of TRAP in health and chronic periodontitis. MATERIALS AND METHODS: The present cross-sectional clinico-biochemical study comprised 30 systemically healthy subjects with 15 periodontally healthy and 15 chronic periodontitis subjects who were age and gender matched. GCF and blood samples were collected from all the patients. TRAP estimation was done in both the samples using an enzyme-linked immunosorbent assay kit. The data were analyzed using independent t-test and Pearson correlation test. RESULTS: Serum and GCF TRAP levels in chronic periodontitis subjects were significantly higher when compared to the periodontally healthy group. There were no significant correlations found among serum and GCF TRAP levels with increasing age and gender in both the groups. An increase in disease severity, i.e., increase in probing pocket depth and clinical attachment level, did not show correlation with the GCF and serum TRAP levels in the chronic periodontitis group. CONCLUSION: Based on the findings of the present study, increased GCF TRAP levels in chronic periodontitis seem to be a potential marker for identifying ongoing periodontal destruction.

A review on ferulic acid and analogs based scaffolds for the management of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related multifactorial neurodegenerative disorder characterized by severe central cholinergic neuronal loss, gradually contributing to cognitive dysfunction and impaired motor activity, resulting in the brain's cell death at the later stages of AD. Although the etiology of AD is not well understood, however, several factors such as oxidative stress, deposition of amyloid-ß (Aß) peptides to form Aß plaques, intraneuronal accumulation of hyperphosphorylated tau protein, and low level of acetylcholine are thought to play a major role in the pathogenesis of AD. There is practically no drug for AD treatment that can address the basic factors responsible for the neurodegeneration and slow down the disease progression. The currently available therapies for AD in the market focus on providing only symptomatic relief without addressing the aforesaid basic factors responsible for the neurodegeneration. Ferulic acid (FA) is a phenol derivative from natural sources and serves as a potential pharmacophore that exerts multiple pharmacological properties such as antioxidant, neuroprotection, Aß aggregation modulation, and anti-inflammatory. Several FA based hybrid analogs are under investigation as a multi-target directed ligand (MTDLs) to develop novel hybrid compounds for the treatment of AD. In the present review article, we are focused on the critical pathogenic factors responsible for the onset of AD followed by the developments of FA pharmacophore-based hybrids compounds as a novel multifunctional therapeutic agent to address the limitations associated with available treatment for AD. The rationale behind the development of these compounds and their pharmacological activities in particular to their ChE inhibition (ChEI), neuroprotection, antioxidant property, Aß aggregation modulation, and metal chelation ability, are discussed in detail. We have also discussed the discovery of caffeic and cinnamic acids based MTDLs for AD. This review paper provides an in-depth insight into the research progress and current status of these novel therapeutics in AD and prospects for developing a druggable molecule with desired pharmacological affinity and reduced toxicity for the management of AD.

Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease.

In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 µM; BChE IC50 = 14.05 ± 0.10 µM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 µM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 µM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid ß1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.

Contrasting Gene Expression Profiles of Monocytes and Lymphocytes From Peste-Des-Petits-Ruminants Virus Infected Goats.

In this study, transcriptome analysis of PPRV infected PBMC subsets-T helper cells, T cytotoxic cells, monocytes, and B lymphocytes was done to delineate their role in host response. PPRV was found to infect lymphocytes and not monocytes. The established receptor for PPRV-SLAM was found downregulated in lymphocytes and non-differentially expressed in monocytes. A profound deviation in the global gene expression profile with a large number of unique upregulated genes (851) and downregulated genes (605) was observed in monocytes in comparison to lymphocytes. ISGs-ISG15, Mx1, Mx2, RSAD2, IFIT3, and IFIT5 that play a role in antiviral response and the genes for viral sensors-MDA5, LGP2, and RIG1, were found to be upregulated in lymphocytes and downregulated in monocytes. The transcription factors-IRF-7 and STAT-1 that regulate expression of most of the ISGs were found activated in lymphocytes and not in monocytes. Interferon signaling pathway and RIG1 like receptor signaling pathway were found activated in lymphocytes and not in monocytes. This contrast in gene expression profiles and signaling pathways indicated the predominant role of lymphocytes in generating the antiviral response against PPRV in goats, thus, giving us new insights into host response to PPRV.

Evaluation of cultivated and wild genotypes of Lens species under alkalinity stress and their molecular collocation using microsatellite markers.

In this study, 285 lentil genotypes were phenotyped under hydroponic and alkaline field conditions. Significant genotypic variation for alkalinity stress was observed among the six Lens species screened hydroponically and in the field having pH up to 9.1. The crucial parameters, like whole Na+ and K+ contents and the Na+/K+ ratio at 40 mM NaHCO3 were found significantly correlated with seedling survivability under hydroponics (r = -0.95, r = 0.93 and -0.97). Genotypes, ranked on the bases of seed yield, restricted uptake of Na+ with thick pith area, increased vascular bundles, less H2O2 production and low Na+/K+ ratio, were found important physio-anatomical traits for alkalinity stress tolerance. The proper regulation of Na+ uptake was found for maintaining higher K+. This relationship is probably the main factor responsible for a better mechanism for tolerance to high pH up to 9.1 in tolerant breeding lines PDL-1 and PSL-9 (cultivars) and ILWL-15, ILWL-192 and ILWL-20 (wild accessions). Based on UPGMA dendrogram, all the genotypes were clustered into four diverse groups. DMRT was implied within the group to differentiate genotypes based on phenotypic response under alkalinity stress. These results can be utilized for selecting diverse parents for developing alkalinity tolerant genotypes.

Dysregulated miRNAome and Proteome of PPRV Infected Goat PBMCs Reveal a Coordinated Immune Response.

In this study, the miRNAome and proteome of virulent Peste des petits ruminants virus (PPRV) infected goat peripheral blood mononuclear cells (PBMCs) were analyzed. The identified differentially expressed miRNAs (DEmiRNAs) were found to govern genes that modulate immune response based on the proteome data. The top 10 significantly enriched immune response processes were found to be governed by 98 genes. The top 10 DEmiRNAs governing these 98 genes were identified based on the number of genes governed by them. Out of these 10 DEmiRNAs, 7 were upregulated, and 3 were downregulated. These include miR-664, miR-2311, miR-2897, miR-484, miR-2440, miR-3533, miR-574, miR-210, miR-21-5p, and miR-30. miR-664 and miR-484 with proviral and antiviral activities, respectively, were upregulated in PPRV infected PBMCs. miR-210 that inhibits apoptosis was downregulated. miR-21-5p that decreases the sensitivity of cells to the antiviral activity of IFNs and miR-30b that inhibits antigen processing and presentation by primary macrophages were downregulated, indicative of a strong host response to PPRV infection. miR-21-5p was found to be inhibited on IPA upstream regulatory analysis of RNA-sequencing data. This miRNA that was also highly downregulated and was found to govern 16 immune response genes in the proteome data was selected for functional validation vis-a-vis TGFBR2 (TGF-beta receptor type-2). TGFBR2 that regulates cell differentiation and is involved in several immune response pathways was found to be governed by most of the identified immune modulating DEmiRNAs. The decreased luciferase activity in Dual Luciferase Reporter Assay indicated specific binding of miR-21-5p and miR-484 to their target thus establishing specific binding of the miRNAs to their targets.This is the first report on the miRNAome and proteome of virulent PPRV infected goat PBMCs.